Compositions and methods for the treatment of hyperlipemia

ABSTRACT

COMPOUNDS OF THE FORMULA   Z-CH2-X-A-X-CH2Z   IN WHICH X IS OXYGEN, SULFUR, SULFINYL, SUYLFONYL OR IMINO, A IS 2-HYDROXYPROPYLENE, ALKYLENE OF 5 TO 10 CARBON ATOMS, PHENYLENE, BIPHENYLENE OR NAPHTHYLENE AND Z IS HYDROXYMETHYLENE, CARBOXY OR CARBO(LOWER ALKOXY) ARE NORMOLIPEMIC AGENTS USEFUL IN THE TREATMENT OF HYPERLIPEMIA. PHARMACEUTICAL COMPOSITION UTILIZING SUCH COMPOUNDS AND THEIR METHOD OF USE ARE DISCLOSED. A TYPICAL EMBODIMENT IS THE USE OF 1,10-BIS(2-HYDROXYETHYLTHIO) DECANE.

United States Patent 3,769,436 COMPOSITIONS AND METHODS FOR THE TREATMENT OF HYPERLIPEMIA Louis Lafon, Rue de lAlboni, Paris 16 eme, France No Drawing. Continuation-impart of abandoned application Ser. No. 60,731, Aug. 3, 1970. This application Oct. 7, 1971, Ser. No. 187,539 Claims priority, application Great Britain, Aug. 8, 1969, 39,894/ 69 Int. Cl. A61k 27/00 US. Cl. 424-337 11 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula ZCH -XA-XCH Z in which X is oxygen, sulfur, sulfinyl, sulfonyl or imino, A is 2-hydroxypropylene, alkylene of 5 to carbon atoms, phenylene, biphenylene or naphthylene and Z is hydroxymethylene, carboxy or carbo(1ower alkoxy) are normolipemic agents useful in the treatment of hyperlipemia. Pharmaceutical compositions utilizing such compounds and their method of use are disclosed. A typical embodiment is the use of 1,IO-bis(Z-hydroxyethylthio) decane.

CROSS REFERENCE This is a continuation-in-part of Ser. No. 60,731 filed Aug. 3, 1970, now abandoned.

DETAILED DESCRIPTION The present invention relates to medicaments particularly useful as normolipemiant agents, comprising at least one compound of the formula:

wherein X is O, NH, S, S0 or S0 A i an alkylene radical containing 5 to 10 carbon atoms, Z-hydroxy-propylene, phenylene, biphenylene and naphthylene, and Z is hydroxymethylene, carboxy or carbo(lower alkoxy).

Compounds of the above formula have action on lipid metabolism and are therefore useful as normolipemiant agents in the treatment of diseases involving metabolic disturbances, as for example arteriosclerosis and coronary artery disorders. In particular the compounds are effective in treating hyperlipemia.

Pharmaceutical compositions incorporating one or more of these compounds in pharmaceutically-acceptable diluents or carriers are thus provided to be administered orally or parenterally to patients in a form suitable for poviding an immediate or a delayed effect.

Suitable daily doses range from 0.5 to 5 g., depending upon the compound utilized, the method of administration, the condition, age and size of the patient, and the response which is sought.

Pharmaceutical compositions can include, in addition to the above compounds, one or more other medicaments having action on lipid metabolism or on vascular disorders such as vitamins, choline, inositol, amino acids and the like.

The compounds of Formula I in which X is O or NH can be prepared by reacting a compound, HXAXH, with two molar equivalents of a monohaloacetic acid or a monohaloacetate in the presence of aqueous caustic soda, or in a solvent medium in the presence of potassium carbonate, at the boiling point of the reaction medium.

The compounds of Formula I in which X is S can be prepared by reactin a halo-A-halo dihalide with two molar equivalents of mercaptoacetic acid or fl-mercaptoethanol in the presence of aqueous caustic soda optionally 3,769,436 Patented Oct. 30, 1973 Ice p-Phenylenedioxy diacetic acid 41.6 g. (0.44 mole) of monochloroacetic acid, ml. of a 40% aqueous caustic soda solution, 500 ml. of water and 22 g. (0.20 mole) of hydroquinone were introduced into a 1 liter flask. The reaction mixture was heated and maintained at the boiling point for 15 minutes. It was then treated with active charcoal and the solution cooled and then acidified. The p-phenylenedioxy diacetic acid which formed and precipitated was recovered by filtration.

After drying, the product obtained in a yield of 69% (31.2 g.) had the form of a fine, a clear-beige powder, the instantaneous melting point of which was 255 256 C. It is insoluble in water, ethanol, ethyl ether and benzene and soluble in aqueous alkaline solutions.

EXAMPLE 2 1,5-bis (carbethoxymethoxy) naphtholene y-o ni-o 0 o 02H,

8 g. (0.05 mole) of 1,S-dihydroxynaphthalene, 16.7 g. (0.10 mole) of ethyl bromoacetate, 16.6 g. (0.1 mole) of potassium iodide, 13.8 g. (0.1 mole) of potassium carbonate and 200 ml. of acetone were introduced into a 500 ml. flask. The reaction mixture was agitated rapidly and heated. The mixture was maintained at the boiling point until the end of the evolution of gas. After cooling, the solvent was eliminated and then the residue was taken up in water and methylene chloride.

The chloromethylene solution, after being washed with a 5% aqueous caustic soda solution and then with water to neutrality, was dried over anhydrous sodium sulfate and then filtered and evaporated. The crude l,5-bis(carbethoxymethoxy)naphthalene [alternatively named as ethyl (naphthalene-1,5-dioxy)-diacetate] thus isolated was purified by crystallization from ethyl acetate. The prodnot, obtained in a yield of 60% (10 g.), had the appearance of a fine yellow powder having an instantaneous melting point of 133 -l34 C. and is insoluble in water,

ethanol, ethyl ether and benzene.

EXAMPLE 3 4,4'-bis carbethoxymethylene) biphenyl tion was washed with a 5% aqueous caustic soda solution and then with water to neutrality, dried over anhydrous sodium sulfate, filtered and then evaporated.

The product, obtained in a yield of 69.8% (12.5 g.), had the appearance of a white crystalline powder, the instantaneous melting point of which is 130-13l C., and it is soluble in methylene chloride and in benzene and is insoluble in water, ethanol and ethyl ether.

EXAMPLE 4 p-Phenylenediamine-N,N'-diacetic acid H 0 C-Cm-HN-Q-NH-CI-L-C 0 on 18 g. (0.19 mole) of monochloroacetic acid in solution in 50 ml. of water was introduced into a 250 ml. flask, followed by a solution of 8.25 g. (0.21 mole) of caustic soda in 10 ml. of water. Then 10 g. (0.09 mole) of pphenylenediamine was added and the mixture was heated to maintain it at the boiling point for about 5 minutes. After cooling, the crude product, alternatively named as N,N-(paraphenylene-diamine)-diacetic acid, which precipitated was recovered by filtration. It was purified by crystallization from water.

The product, obtained in a yield of 54.4% (9.4 g.), had the appearance of a beige crystalline powder, having an instantaneous melting point of 222-228 C., and is soluble in dilute aqueous acid and alkaline solutions and is insoluble in water, ethanol, ethyl ether and benzene.

EXAMPLE 5 1,5 -bis fl-hydroxyethylthio) -pentane HOCH CH S (CH SCH ,CH OH 69 g. (0.30 mole) of 1,5-dibromopentane, 51.6 g. (0.66 mole) of Z-mercaptoethanol were introduced into a 500 ml. flask and then 67 ml. of a 40% aqueous caustic soda solution was added. The temperature rose. The mixture was then heated to the boiling point for 2 hours. After cooling, the mixture was taken up in water and the 1,5- bis(}8-hydroxyethylthio)pentane which formed was extracted with ethyl ether. The ethereal solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated.

The product, obtained in a yield of 63.6% (42.7 g.), had the appearance of a clear yellow oil which, on cooling, formed crystals having a melting point of 25 -3 0 C.; the product is soluble in ethanol, ethyl ether and benzene and insoluble in water.

EXAMPLE 6 1,l0-bis(/8-hydroxyethylthio) decane HOCH CH S-(CH --SCH -CH OH 30 g. (0.10 mole) of 1,10-dibromodecane, 17.2 g. (0.22 mole) of 2-mercaptoethanol and 50 ml. of ethanol were introduced into a 250 ml. flask. Then, 22 ml. of a 40% aqueous caustic soda solution was slowly added. The temperature rose progressively during the operation and reached the boiling point of the solvent, where it was then maintained for about 1 hour. After cooling, the solvent was evaporated under reduced pressure and the residue was taken up in water and methylene chloride. The chloromethylene solution was washed with water, dried over anhydrous sodium sulfate, filtered and then evaporated.

The crude 1,10-bis(fi-hydroxyethylthio) decane thus isolated was purified by crystallization from a water/methanol mixture.

The product, obtained in a yield of 98.3% (29 g.), had the appearance of a white, yellow-reflecting crystalline powder, having an instantaneous melting point of 70- 71 C., and is soluble in ethanol and insoluble in water, ethyl ether and benzene.

4 EXAMPLE 7 1, 1 O-bis B-hydroxyethylsulfinyl) decane nocn cn -so-rcn -SO-CH CH OH 14.7 g. (0.05 mole) of l,10-bis(fl-hydroxyethylthio) decane described in Example 6 was dissolved in 150 ml. of acetic acid in a 250 ml. phial. Then 9.75 ml. of 30% hydrogen peroxide was added. The temperature rose to 40 C. It was allowed to return to ambient temperature and agitation was elfected for 24 hours. The solvent was then evaporated and the pasty residue was taken up in isopropyl ether.

After filtration and drying, the product obtained in a yield of (12.2 g.) had the appearance of a white yellow-reflecting powder, the instantaneous melting point of which was 11l-112 C., and it is soluble in ethanol and water and is insoluble in ethyl ether and benzene.

EXAMPLE 8 1,10-bis( B-hydroxyethylsulfonyl) decane HOCH CH -SO CH -SO CH -CH OH 14.7 g. (0.05 mole) of 1,10-bis(fi-hydroxyethylthio) decane and 150 ml. of acetic acid were introduced into a 250 ml. flask. After dissolution, 25 ml. of 30% hydrogen peroxide was added and the mixture was heated for 16 hours at approximately 60 C. After cooling, the mixture was filtered.

The product, obtained in a yield of 36% (6.45 g.), had the appearance of a white crystalline powder, the instantaneous melting point of which was 109-110 C., and it is insoluble in water, ethanol, ethyl ether and benzene.

EXAMPLE 9 1,3 -bis carb oxymethylthio) propanol-2 12.9 (0.10 mole) of 1,3-dichloropropanol-2, 21.3 g. (0.22 mole) of thioglycolic acid and 100 ml. of ethanol were introduced into a 500 ml. flask. Then 44 ml. of a 40% aqueous caustic soda solution was slowly added. The temperature rose. The mixture was allowed to cool, the solvent was evaporated and the residue was taken up in water, which was then washed with ethyl ether. The aqueous solution was treated with vegetable charcoal and then acidified by the addition of hydrochloric acid and extracted with ethyl ether. The ethereal solution was dried over anhydrous sodium sulfate, filtered and then evaporated.

The product, obtained in a yield of 46% (10.8 g.), had the appearance of a pale yellow oil which was soluble in ethanol, ethyl ether, benzene and aqueous alkaline solutions and is insoluble in water.

EXAMPLE 10 1,5-dithiopentane diacetic acid HOOCCH -S (CH -S-CH CO OH 23 g. (0.10 mole) of 1,5-dibromopentane, 21.3 g. (0.22 mole) of thioglycolic acid and 100 m1. of ethanol were introduced into a 500 ml. flask. Then 44 ml. of a 40% aqueous caustic soda solution was added. The temperature rose. It was then allowed to cool. The reaction medium was washed with ethyl ether. The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl ether to obtain the 1,5-dithiopentane diacetic acid which formed. The ethereal solution, after being washed with water, was dried over anhydrous sodium sulfate, filtered and then evaporated.

The product, obtained in a yield of 89.5% (22.9 g.), had the appearance of a white powder, the instantaneous melting point of which was around C., and it is a soluble in ethanol, ethyl ether and aqueous alkaline solutions and is insoluble in water and in benzene.

6 EXAMPLE 11 Food enriched with lipids (HL) used to provoke hyper- Tablet lipemia in the animals included the following:

Ingredient: Amount per tablet, g. Casein Farce; 1,10-bis(Z-hydroxyethylthio)decane Glucose u Microcrystalline Cellulose 5 t h """I'IIII""11:11:11: 13.4 2:21 :5 Salt of saccharm g Vegetable and animal fats 3 Cellulose 5 Magnesium stearate Q- Mineral material 10 The foregoing materials were compounded and pressed 10 Vitamin complex 1 into 0.59 tablets. Cholesterol 4.5

EXAMPLE 12 P.T.U. 0.3

D Test group No. 1 served as a normal control, received Drages cores were prepared from the following inthe norfnal diet and dflnklng Water ad as Well as a gradients: 15 small piece of bread.

core Amount p core g Test group No. 2 was fed the hyperlipemic diet and 1 water as desired with a piece of bread. 11o'blS(ls-hydroxyethylsulfinyl)decane 0250 Test group No. 3 received the same diet as Test group Lactose 0'050 No. 2 together with the test compound. sugar 0030 Each test lasted 15 days, after which the animals were Magneslum Stearate 0-003 sacrificed by jugular bleeding and the blood was collected Talc (mm for the following biological determinations:

These cores were then coated with the following (a) Total lipids were determined according to the procegredients: r dure of Jobin and Yvon, Instrumental Bulletin (February 1965);

Coating: Amount per coating, (b) Total cholesterol was determined according to the Sugar 0165 technique of L. Babson and Coll. Cl1n1ca Ch1m1ca Acta, Talc 0.070 1962;

Gelatin Trace 30 (c) Burstem evaluation was conducted w1tl1 dextran sul- Titanium Oxide Trace fate, according to the method of l 3ad1n and C011, Ann. WaX Trace BlOl. Cl1n., 1957, 469, Path. et BioL, 1958, p. 541.

The following table shows the results obtained with The resultant drages weigh about 0.59 g. the representative compounds:

TABLE Total lipids Cholesterol Burstein test Dose, Percent Percent Venes Percent Compound Diet nag/kg. G./L. inhib. G./L. inhib. degrees inhib.

Example 5 N 5.0 0.6 25 HL 0 10.4 2. 54 89 HL 500 7. 2 59 1. 54 51 52. 5 56 Examplefi N 0 4.03 0.53 27 HL 0 12.34 2.31 100 HL 125 6. 95 e5 1. 24 e1 HL 250 7. 2s 62 1. 22 02 52 Example 7 N 0 3.1 0.4 23 HL 0 18.8 3.56 170 HL 500 9. 0 65 1.60 62 78 Example 8 N 0 3.1 0.4 23 HL 0 18.8 3.56 170 HL 500 9.6 as 1. 50 65 87 57 EXAMPLE 13 50 The toxicity of the compounds is low with no toxic T bl effects being observed in laboratory animals at oral doses Ingredient; Amount per bl as high as 3000 mg./kg. No evidence of stomach inflam- 1,10-bis(fi-hydroxyethylsulfonyl)decane 0.400 matlon has been Observed- .Sodium salt f Saccharin Q0008 The compound of Example 6 was administered in the Microcrystanine 11 1 095g form of gelules containing 150 mg. of active ingredient Starch Q to 10 classified hyperlipemic patients on adequate diets, Magnesium steal-ate at a dose regimen of 4 to 8 gelules per day for a period The monolipemic effects of the compounds of the presof from 3 Weeks to 5 The composltlon Proved ent invention can be Observed from the following: to have excellent tolerance with no secondary effects. Male rats, of Wistar Strain, of the same Stack and Favorable effects were observed in 7 pat1ents (70%) with weighing between 150 and 200 g. were used in lots of 5 and housed in individual cages maintained at constant temperature.

Either normal food or food enriched with lipids was given ad lib, together with water and a piece of bread. Normal food (N) intended for the control animals, was constituted by biscuits of the following composition:

an average reduction in total lipids of about 15%, of total cholesterol of about 20%, and of the triglycerides of about 16%. Known hypolipemic products have comparable effects, e.g. on the order of a 10 to 18% reduction in total lipids and total cholesterol, in about 40 to of the cases.

What is claimed is:

1. A pharmaceutical composition for the treatment of hyperlipemia comprising in solid oral unit dosage form an effective amount of a compound of the formula:

wherein X is sulfur, sulfinyl or sulfonyl;

A is alkylene of from to 10 carbon atoms; and Z is hydroxymethylene, and a pharmaceutical carrier.

2. The composition according to claim 1 in which said compound is 1,5-bis (,B-hydroxyethylthio)pentane.

3. The composition according to claim 1 in which said compound is 1,10-bis(fl-hydroxyethylthio)decane.

4. The composition according to claim 1 in which said compound is 1,10-bis(fl-hydroxyethylsulfinyl) decane.

5. The composition according to claim 1 in which said compound is 1,10-bis(B-hydroxyethylsulfonyl)decane.

6. A pharmaceutical composition according to claim 1 containing 1,10-bis(,B-hydroxyethylthio)decane as said compound in an amount sufiicient to supply a total daily dosage of from 600 to 1200 mg. thereof upon daily oral administration of a plurality of said dosage forms.

7. The method of treating hyperlipemia which comprises orally administering to a hyperlipemic animal an etfective amount of a compound of the formula:

A is alkylene of 5 to 10 carbon atoms; and Z is hydroxymethylene.

8. The method according to claim 7 in which said compound is 1 S-bis (fl-hydroxyethylthio pentane.

9. The method according to claim 7 in which said compound is 1,10-bis (B-hydroxyethylthio) decane.

10. The method according to claim 7 in which said compound is 1,10-bis(B-hydroxyethylsulfinyl)decane.

11. The method according to claim 7 in which said compound is 1,10-bis(B-hydroxyethylsulfonyl)decane.

References Cited Chem. Abst., vol. 14140-14141 (1961). Chem. Abst., vol. 56-15082b (1962). Chem. Abst., vol. 6116228c (1963).

STANLEY L. FRIEDMAN, Primary Examiner US. Cl. X.R. 

